Most human protein therapeutics require frequent dosing due to rapid clearance of the proteins from the body. Development of second generation protein pharmaceuticals that can be injected less frequently is of considerable interest to patients and healthcare providers. We propose to create long-acting forms of growth hormone, granulocyte colony stimulating factor and erythropoietin by creating larger versions of these proteins with longer circulating half-lives. These modified proteins will possess biological activities equal or superior to the corresponding natural proteins in vivo, but will require less frequent dosing, on the order of once every two to four weeks, rather than daily or every other day. During Phase l we constructed the fusion proteins and demonstrated that certain of them possess wild type in vitro bioactivities. During Phase II, we will manufacture sufficient quantities of the modified proteins for pharmacokinetic and animal efficacy studies. The improved characteristics of the novel proteins will reduce the amount of protein required per patient, improve patient compliance and quality of life and result in considerable cost savings to patients and healthcare providers. These proteins will find utility in treating endocrine and hematopoietic disorders, and complications of AIDS and cancer chemotherapy. PROPOSED COMMERCIAL APPLICATION: Recombinant human Growth Hormone, G-CSF and EPO are used to treat short stature, cachexia, neutropenia and anemia and had world-wide sales in excess of $5 billion in 1997. Long-acting forms of these proteins will require much less frequent dosing than existing products, providing significant cost savings to patients and healthcare providers. Additional potential benefits include improved drug efficacy and improved patient quality of life.